The link between the "king of cancer" and how long a patient survives

Researchers at the Johns Hopkins School of Medicine found that the tissue of different types of immune cells in pancreatic tumors is associated
with how well pancreatic cancer patients respond to treatment and survive time.
The new findings, published Sept.
16 in the journal Cancer Research, could eventually lead to new approaches to treating pancreatic cancer, which has the highest
mortality rate of all major cancers.

Dr Aleksander Popel, professor of biomedical engineering, director of the Systems Biology Laboratory at Johns Hopkins University School of Medicine and member of the Sidney Kimmel Cancer Center at Johns Hopkins University, said: "Mapping the location of certain immune cells associated with tumors could be a new biomarker
for predicting patient survival.
We hope that our findings will not only provide a better understanding of cancer at its roots, but also have the potential to provide prognostic guidance
for clinicians treating pancreatic cancer.
" ”

The National Cancer Institute estimates that by 2022, more than 62,000 Americans are expected to be diagnosed with pancreatic cancer, and nearly 50,000 will die from the disease
.
On average, only 10% of pancreatic cancer patients live past 5 years
.
It is difficult to predict which patients are most likely to respond to the few treatments available; Researchers have long been looking for more tools — cells, molecules or genes — to stratify
pancreatic cancer patients based on survival rates.

In recent years, scientists studying a wide variety of cancers have discovered the importance of non-cancerous cells, molecules and blood vessels around tumors, known as the tumor microenvironment
.
Part of the tumor microenvironment is immune cells; Some of them have the ability to target tumors to destroy tumors, while others help tumors evade the immune system
.

In previous pancreatic cancer studies, researchers counted the number of immune cells present in the tumor microenvironment and found no association with patient prognosis, but Popel and Johns Hopkins graduate student Haoyang Mi hypothesized that the physical arrangement of immune cells might be more important
than the total.

In the new study, Popel, Mi, and collaborators at Oregon Health and Science University used a method called multiple immunohistochemistry to precisely locate the locations
of 27 different immune molecules from 45 patients with pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer.
52% of the patients were women, with an average age of 63.
5 years, with cancer at all stages, with 41% of the participants' cancers spreading to at least 4 lymph nodes
.

These molecules — found in different combinations on the surface of different types of immune cells — correspond to the relative locations
of immune cell subtypes.
They then developed new computational algorithms to analyze how the number, location, and shape of these cells changed between patients with survival times greater than or less than the median survival time of
619 days.

"Through the computational methods we developed, we analyzed not only the density of each cell type, but also how they interact in the spatial structure of tumors," said
Mi, first author of the new paper.

The researchers found that among the 22 patients who survived less than average (median 313 days), immune cells called IL-10+ myeloid monocytes tended to be located near
clusters of granase B+ CD8+ T cells (or cytotoxic T lymphocytes).
In 23 patients who survived longer than average lifespan (median 832 days), the same myeloid monocytes more clustered near another type of T cell, namely PD-1+ CD4+ T cells (or activated helper T cells
).

Based on what we know about the function of these immune cells, the results make sense
, Mi said.
Each cell type is like the brakes
on another.
Cytotoxic T lymphocytes produce a toxin that kills cancer cells, but in patients who survive short-term, the researchers hypothesized that nearby bone marrow monocytes would block this ability
.
However, in long-lived patients, they believe that activated helper T cells shut down the medullary mononuclear cells, which in turn allowed cytotoxic T lymphocytes to fight cancer
more effectively.

More research is needed to validate these hypotheses about how cells interact in the pancreatic tumor microenvironment, as well as to determine whether targeting any one cell type leads to new pancreatic cancer immunotherapies
, the researchers said.
But the researchers hope that further research will confirm that the association of the tumor microenvironment with survival can provide clinicians with prognostic information and may direct patients to specific treatments or clinical trials
.

Haoyang Mi, Shamilene Sivagnanam, Courtney B.
Betts, Shannon M.
Liudahl, Elizabeth M.
Jaffee, Lisa M.
Coussens, Aleksander S.
Popel.
Quantitative Spatial Profiling of Immune Populations in Pancreatic Ductal Adenocarcinoma Reveals Tumor Microenvironment Heterogeneity and Prognostic Biomarkers.
Cancer Research, 2022; DOI: 10.
1158/0008-5472.
CAN-22-1190